Cryptococcal meningitis carries a high mortality despite available therapy; moreover, the population of patients at risk is expanding due to increasing use of immunosuppressive and cytotoxic drugs. Previously described models of cryptococcal infection in mice and guinea pigs have the disadvantage that CSF cannot be obtained in useful quantities, while cats and large animals are inconvenient to handle. We have developed a practical model for cryptococcal meningitis in steroid-treated rabbits. Normal rabbits injected intrathecally with cryptococci eradicate the yeasts in 1-2 weeks, but cortisone-treated animals develop chronic cryptococcal meningitis which is fatal in 2-6 weeks. The objectives of this project are to apply this model to studies of pathogenesis and treatment of chronic meningitis. First, the natural history of cryptococcal meningitis in rabbits will be further defined. The effects of varying cortisone dose and dose-interval, the virulence of different strains of cryptococci, and the effect of preimmunization with polysaccharide antigen will be evaluated. The reasons for failure of polymorphonuclear leukocytes to accumulate in CSF will be examined by testing for chemotactic activity in CSF. Second, the cellular immune response will be studied in normal and cortisone-treated rabbits. We have already found that lymphocyte accumulation is deficient in CSF of infected, cortisone-treated animals. The subpopulations and functional capacity of lymphocytes in blood and CSF will be determined. Experiments will be conducted to detect suppressor cells, and to evaluate lymphocyte-macrophage interactions during infection. Third, the model will be used to evaluate various therapeutic regimens. Relative efficacies of amphotericin B (AMB), amphotericin B methyl ester (AME), 5-fluorocytosine (5FC), combinations of AMB, AME and 5FC, and of Ketoconazole will be compared. Results of therapy will be assessed by serial cultures, detection of antigen and antibody, assay of concentrations of antifungal agents in CSF and blood, and by comparing mortality among the treatment groups.